NFE2L3

NFE2L3
Identifiers
Aliases NFE2L3, NRF3, nuclear factor, erythroid 2 like 3
External IDs MGI: 1339958 HomoloGene: 3168 GeneCards: NFE2L3
Orthologs
Species Human Mouse
Entrez

9603

18025

Ensembl

ENSG00000050344

ENSMUSG00000029832

UniProt

Q9Y4A8

Q9WTM4

RefSeq (mRNA)

NM_004289

NM_010903

RefSeq (protein)

NP_004280.5

NP_035033.1

Location (UCSC) Chr 7: 26.15 – 26.19 Mb Chr 6: 51.43 – 51.46 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Nuclear Factor (Erythroid 2) - Like Factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.[3][4]

This protein is a basic leucine zipper transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins.[5] In 1989, the first CNC transcription factor was identified, namely NFE2L2. After that, several other protein members have also been identified over the years like NRF1 and NRF3 in different organisms like humans, mice and zebrafish.[6] These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.[7][8]

Gene

The mapping of Nfe2l3 gene by Fluorescence In-Situ Hybridisation (FISH) technique revealed its chromosomal location being 7p15-p14.[7] It covers 34.93 kB from 26191830 to 26226754 on the direct DNA strand with an exon count of 4. The gene maps near the HOXA gene cluster which is similar to the genetic loci of p45 NFE2, NFE2L1 and NFE2L2 and are further clustered around HOXC, HOXB and HOXD genes respectively.[5][7] This information tells us that all these genes have been derived from a single ancestral gene which is closely localised to HOX cluster and from there, these genes have diverged to four closely related transcription factors.[7]

The human NFE2L3 encodes for a 694 base pairs amino acid protein.[5][7] From Bioinformatics analysis, it has been observed that NFE2L3 protein shows a high degree of conservation through its evolutionary pathway from zebrafish to humans having key domains like N-terminal Homology Box 1 (NHB1), N-terminal Homology Box 2 (NHB2) and CNC domain. These conserved domains help to identify the functional properties of this protein.[9]

Sub-Cellular Location

NFE2L3 is a membrane bound glycoprotein that is targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane.[7] From biochemical studies, it has been seen that there are three different migrating endogenous forms of NFE2L3 protein which are essentially short lived - the first one being migrating "A" form, the second one being an intermediate "B" form and the third one being a fast migrating "C" form.[7] Using PNGase F and Endoglycosidase H enzymes, it was revealed that "A" form is glycosylated whereas "B" and "C" forms are unglycosylated.[5][7] In total, seven potential sites of N-linked glycosylation [5] has been observed in the centre portion of this NFE2L3 protein, however the exact information on each of the forms are yet to be identified.

Protein Expression Levels

The expression levels of NFE2L3 proteins are found to be highest in placenta.[10] more specifically in the chorionic villi (at week 12 of gestation period) [11] The expression levels are more common in primary placental cytotrophoblast, but not in placental fibroblasts. Along with the placenta, the expression of this protein has also been observed in human choriocarcinoma cell lines which have been derived from trophoblastic tumours found in the placenta. Other variety of tissue regions that have experienced the expression of NFE2L3 protein has been Heart, Brain, Lungs, Kidney, Pancreas, Colon, Thymus, Leukocytes as well as Spleen.[12] Very low levels of expression were found in case of Human Megakaryocytes and Erythrocytes whereas no expression was found in case of reproductive organs found in both the sexes.[7][13]

Function

The specific functions of NFE2L3 protein are still unknown, but since the structural information has been found to be similar to that of NFE2L1 protein, some functional properties can be deciphered from that.

This encoded protein NFE2L3 heterodimerizes with small musculo-aponeurotic fibro-sarcoma (MAF Genes) factors to bind antioxidant response elements in target genes.[14] Several in vivo data has revealed that NFE2L3 is known to protect the body against carcinogen-induced lymphomagenesis. But, not enough information has been derived and researchers are still working on it.

Recently, a few reports have opened new avenues for NFE2L3 protein. But, all these proposals are still in its niche stage and needs concrete evidences to reveal its actual functionality.

Associated diseases

A series of Gene chip analysis array data of NFE2L3 has shown its involvement in various malignancies with over-expressions like Hodgkin Lymphoma, Non-Hodgkin lymphoma cell lineages and Mantle cell lymphoma.[15] Along with that, there has also been an up-regulation of mRNA levels in human breast cancer cells and testicular carcinoma tissues which reveals that NFE2L3 plays a role in inducing carcinogenesis.[16]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ "Entrez Gene: nuclear factor (erythroid-derived 2)-like 3".
  4. ↑ Kobayashi A, Ito E, Toki T, Kogame K, Takahashi S, Igarashi K, Hayashi N, Yamamoto M (March 1999). "Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3". The Journal of Biological Chemistry. 274 (10): 6443–52. doi:10.1074/jbc.274.10.6443. PMID 10037736.
  5. 1 2 3 4 5 Landschulz WH, Johnson PF, McKnight SL (June 1988). "The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins". Science. 240 (4860): 1759–64. doi:10.1126/science.3289117. JSTOR 1701639. PMID 3289117.
  6. ↑ Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V (April 2004). "Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus". Molecular and Cellular Biology. 24 (8): 3286–94. doi:10.1128/mcb.24.8.3286-3294.2004. PMC 381672Freely accessible. PMID 15060151.
  7. 1 2 3 4 5 6 7 8 9 Chevillard G, Blank V (October 2011). "NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors". Cellular and Molecular Life Sciences. 68 (20): 3337–48. doi:10.1007/s00018-011-0747-x. PMID 21687990.
  8. ↑ Caterina JJ, Donze D, Sun CW, Ciavatta DJ, Townes TM (June 1994). "Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression". Nucleic Acids Research. 22 (12): 2383–91. doi:10.1093/nar/22.12.2383. PMC 523699Freely accessible. PMID 8036168.
  9. ↑ Xiao Q, Pepe AE, Wang G, Luo Z, Zhang L, Zeng L, Zhang Z, Hu Y, Ye S, Xu Q (March 2012). "Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (3): 730–44. doi:10.1161/ATVBAHA.111.243188. PMID 22247257.
  10. ↑ Chénais B, Derjuga A, Massrieh W, Red-Horse K, Bellingard V, Fisher SJ, Blank V (January 2005). "Functional and placental expression analysis of the human NRF3 transcription factor". Molecular Endocrinology. 19 (1): 125–37. doi:10.1210/me.2003-0379. PMID 15388789.
  11. ↑ Chevillard G, Paquet M, Blank V (February 2011). "Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma". Blood. 117 (6): 2005–8. doi:10.1182/blood-2010-02-271460. PMID 21148084.
  12. ↑ Martín-Montalvo, A.; Villalba, J. M.; Navas, P.; de Cabo, R. (3 February 2011). "NRF2, cancer and calorie restriction". Oncogene. 30 (5): 505–520. doi:10.1038/onc.2010.492. ISSN 1476-5594. PMC 4684645Freely accessible. PMID 21057541.
  13. ↑ Venugopal R, Jaiswal AK (December 1998). "Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes". Oncogene. 17 (24): 3145–56. doi:10.1038/sj.onc.1202237. PMID 9872330.
  14. ↑ Blank V, Andrews NC (November 1997). "The Maf transcription factors: regulators of differentiation". Trends in Biochemical Sciences. 22 (11): 437–41. doi:10.1016/s0968-0004(97)01105-5. PMID 9397686.
  15. ↑ Willenbrock K, Küppers R, Renné C, Brune V, Eckerle S, Weidmann E, Bräuninger A, Hansmann ML (May 2006). "Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma". Haematologica. 91 (5): 596–604. PMID 16670065.
  16. ↑ Hayes JD, McMahon M (December 2001). "Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention". Cancer Letters. 174 (2): 103–13. doi:10.1016/s0304-3835(01)00695-4. PMID 11689285.

Further reading

  • Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M (April 2010). "New genetic associations detected in a host response study to hepatitis B vaccine". Genes and Immunity. 11 (3): 232–8. doi:10.1038/gene.2010.1. PMID 20237496. 
  • Sankaranarayanan K, Jaiswal AK (December 2004). "Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene". The Journal of Biological Chemistry. 279 (49): 50810–7. doi:10.1074/jbc.M404984200. PMID 15385560. 
  • Chénais B, Derjuga A, Massrieh W, Red-Horse K, Bellingard V, Fisher SJ, Blank V (January 2005). "Functional and placental expression analysis of the human NRF3 transcription factor". Molecular Endocrinology. 19 (1): 125–37. doi:10.1210/me.2003-0379. PMID 15388789. 
  • Nouhi Z, Chevillard G, Derjuga A, Blank V (November 2007). "Endoplasmic reticulum association and N-linked glycosylation of the human Nrf3 transcription factor". FEBS Letters. 581 (28): 5401–6. doi:10.1016/j.febslet.2007.10.041. PMID 17976382. 
  • Terui K, Takahashi Y, Kitazawa J, Toki T, Yokoyama M, Ito E (December 2000). "Expression of transcription factors during megakaryocytic differentiation of CD34+ cells from human cord blood induced by thrombopoietin". The Tohoku Journal of Experimental Medicine. 192 (4): 259–73. doi:10.1620/tjem.192.259. PMID 11286316. 
  • "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–108. November 1998. doi:10.1101/gr.8.11.1097. PMID 9847074. 
  • Zhang Y, Kobayashi A, Yamamoto M, Hayes JD (January 2009). "The Nrf3 transcription factor is a membrane-bound glycoprotein targeted to the endoplasmic reticulum through its N-terminal homology box 1 sequence". The Journal of Biological Chemistry. 284 (5): 3195–210. doi:10.1074/jbc.M805337200. PMID 19047052. 

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